Different effects of AT1 receptor antagonist and ET(A) receptor antagonist on ischemia-induced norepinephrine release in rat hearts

Angiotensin type 1 receptor (AT1R) antagonist and endothelin type A receptor (ET(A)R) antagonist were compared as regards their effects on ischemia-induced exocytotic or carrier-mediated norepinephrine (NE) release from cardiac sympathetic nerve endings. According to the Langendorff technique, isolated rat hearts were subjected to 20-minute or 40-minute global ischemia followed by 30-minute reperfusion. Candesartan (selective AT1R antagonist) and ABT-627 (selective ET(A)R antagonist) were perfused, beginning 15 minutes before ischemia. Candesartan (10 and 100 nM) and ABT-627 (3 μM) suppressed excessive NE overflow (exocytotic release) in the coronary effluent from the heart exposed to 20-minute ischemia. In addition, these agents improved postischemic cardiac dysfunction. On the other hand, the beneficial effects of ABT-627 (1 and 3 μM) on NE overflow (carrier-mediated release) and cardiac dysfunction were also observed in 40-minute ischemia, whereas those were not improved by treatment with candesartan (10 and 100 nM and 1 μM). These findings suggest that both AT1R antagonist and ET(A)R antagonist have ability to inhibit the exocytotic NE release, but the carrier-mediated NE release induced by prolonged ischemia cannot be avoided by AT1R antagonist. Thus, ET(A)R antagonist may be more useful than AT1R antagonist in the clinical settings of ischemic heart disease.     

Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in Japan

Genetic polymorphisms of enzymes involved in the metabolism of carcinogens are suggested to modify an individual's susceptibility to lung cancer. The purpose of this study was to investigate the relationship between lung cancer cases in Japan and variant alleles of cytochrome P450 (CYP) 2A6 (CYP2A6*4), CYP2A13 (CYP2A13*1-*10), CYP4B1 (CYP4B1*1-*7), sulfotransferase 1A1 (SULT1A1*2), glutathione S-transferase M1 (GSTM1 null), and glutathione S-transferase T1 (GSTT1 null). We investigated the distribution of these polymorphisms in 192 lung cancer patients and in 203 age- and sex-matched cancer-free controls. The polymorphisms were analyzed using various techniques including allele-specific PCR, hybridization probe assay, multiplex PCR, denaturing high-performance liquid chromatography (DHPLC), and direct sequencing. We also investigated allele and genotype frequencies and their association with lung cancer risk, demographic factors, and smoking status. The prevalence of the CYP2A6*4/*4 genotype in lung cancer cases was 3.6%, compared with 9.4% in the controls (adjusted OR = 0.36, 95% CI = 0.15-0.88, P = 0.025). In contrast, there was no association between the known CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1 polymorphisms and lung cancer. These data indicate that CYP2A6 deletions may be associated with lung cancer in the Japanese population studied.     

A combination of interleukin-6 and its soluble receptor impairs sperm motility: implications in infertility associated with endometriosis

BACKGROUND: We previously reported that the level of interleukin (IL)-6 is increased in the peritoneal fluid of women with endometriosis. This study was undertaken to assess the effects of IL-6 and soluble IL-6 receptor (sIL-6R) on in vitro sperm motility. METHODS: Sperm (n = 20) were cultured with IL-6 or sIL-6R, or with a combination of both. After 24 h cultures, sperm motility was evaluated using a computer-assisted semen analysis system. Gene and protein expressions of IL-6, IL-6 receptor (IL-6R), and glycoprotein 130 (gp130) were examined in sperm by RT-PCR analysis and western blot analysis. RESULTS: Addition of IL-6 or sIL-6R individually to the culture media had no affect on sperm motion. However, adding a combination of IL-6 and sIL-6R dose-dependently reduced the percentage of motile and rapidly moving sperm. Adding anti-IL-6R antibody abolished these adverse effects. Sperm expressed the gp130 gene and protein, but not IL-6 or IL-6R. CONCLUSIONS: A combination of IL-6 and sIL-6R may be associated with gp130 expressed in the sperm and reduce sperm motility. IL-6 and sIL-6R may contribute to the pathogenesis of endometriosis-associated infertility.     

Thalamic hypometabolism on 18FDG-positron emission tomography in medial temporal lobe epilepsy

OBJECTIVES: Degree of hypometabolism in the thalamus on (18)Fluorodeoxyglucose-positron emission tomography (FDG-PET) was compared with those of medial and lateral temporal lobes in patients with medial temporal lobe epilepsy (mTLE), and its relationship with post-operative seizure outcomes was investigated. METHODS: Twenty-six patients with mTLE who underwent anterior temporal lobectomy were included. Post-operatively, 13 patients became completely seizure-free and 13 showed residual seizure, regardless of frequency (five patients became almost seizure-free, six had rare seizures and two showed significant improvements). Degrees of hypometabolism in bilateral thalamus, ipsilateral medial and lateral temporal lobes were evaluated visually and semi-quantitatively by determining the asymmetry index (AI), a value indicating 100 x (ipsilateral - contralateral)/[1/2 x (ipsilateral + contralateral)] and the region-to-cerebral hemisphere ratio (R/C ratio) being the ratio between averaged counts in each area and those in the cerebral hemisphere of the same side. RESULTS: Hypometabolism in the medial temporal lobe was visually observed in all patients. Hypometabolism in the lateral temporal lobe was observed in 20 patients and was semi-quantitatively more prominent than that of the medial temporal lobe. Pathologically, hippocampal sclerosis and prominent astrogliosis of the lateral temporal lobe were present in all cases. However, while thalamic hypometabolism was visually observed in nine patients (in the ipsilateral side of four cases, contralateral side of three and on both sides of two), no significant thalamic hypometabolism was semi-quantitatively observed. No significant differences in metabolic rate in any area except for the lateral temporal lobe between seizure-free patients and residual seizure patients were seen semi-quantitatively. DISCUSSION: Data indicated that metabolism in the lateral temporal lobe of patients with mTLE significantly decreased and revealed pathologic glial changes. Thalamic hypometabolism was quite mild and did not correlate with post-operative seizure outcome.     

Fetal germinal matrix and intraventricular hemorrhage

Subependymal germinal matrix with intraventricular hemorrhage (GMIVH) is a common complication associated with delivery in preterm neonates but has rarely been observed in the fetus. Clinical and neuroradiological findings of 5 patients who were diagnosed as having fetal GMIVH with prenatal ultrasonographic examinations (US) and MRI, and postnatal MRI were reviewed retrospectively. During a seemingly uneventful pregnancy, fetal GMIVH occurred at approximately 30-33 weeks of gestation, with the absence of any known factor predisposing to fetal hemorrhage. Routine obstetric US revealed an intraventricular lesion in the enlarged ventricles. Prenatal MRI clearly demonstrated parenchymal change such as intracerebral hematoma adjacent to the subependymal and intraventricular hematoma, and periventricular leukomalacia as well as GMIVH. Although patients without parenchymal destruction (hemosiderin deposit alone) had a favorable neurodevelopmental outcome, encephalomalacia and periventricular leukomalacia contributed to long-term neurodevelopmental deficits. Evaluating parenchymal damage with prenatal MRI can therefore help to predict neurodevelopmental prognosis of the fetus with GMIVH.     

Effects of nocturnal bright light on saliva melatonin, core body temperature and sleep propensity rhythms in human subjects

Nine healthy male volunteers (mean age of 24) participated in two experimental sessions of random crossover design: a bright light (5000 lux for 5 h from 00:00 to 05:00 h) session and a dim light (10 lux for 5 h from 00:00 to 05:00 h) session. Subsequently participants entered an ultra-short sleep-wake schedule for 26 h, in which a sleep-wake cycle consisting of 10-min sleep EEG recording on a bed and 20-min resting awake on a semi-upright chair were repeated. Saliva melatonin level and core body temperature was measured throughout the experiment. Bright light significantly delayed rhythms of melatonin secretion (01:58 h), core body temperature (01:12 h) and sleep propensity (02:00 h), compared as dim light session. Significant positive correlation was found between bright light-induced phase change in core body temperature and that in sleep propensity rhythm. Light-induced melatonin suppression significantly positively correlated with the phase change in core body temperature and that in sleep propensity rhythm. Assuming that light-induced melatonin suppression represents an acute impact of light on the circadian pacemaker, our results suggest that such an impact may be directly reflected in phase changes of sleep propensity and core body temperature rhythms rather than in melatonin rhythm.     

Agonist pharmacology at recombinant α1A- and α1L-adrenoceptors and in lower urinary tract α1-adrenoceptors

BACKGROUND AND PURPOSE

Two distinct α₁-adrenoceptor phenotypes (α_1A and α_1L) have recently been demonstrated to originate from a single α_1A-adrenoceptor gene. Here, we examined the agonist profiles of recombinant α_1A and α_1L phenotypes and of lower urinary tract (LUT) α₁-adrenoceptors.

EXPERIMENTAL APPROACH

A series of drugs (A61603, Ro 115–1240, NS-49, MK017 and ESR1150) originally developed for stress urinary incontinence (SUI) therapy were used to stimulate recombinant α_1A- and α_1L-adrenoceptor phenotypes, and their potencies and intrinsic activity estimated from Ca²⁺ responses. Agonist-induced contractions were also examined in LUT tissues of rats and humans and in human mesenteric artery and rat tail artery.

KEY RESULTS

All the drugs were potent agonists of the α_1A-adrenoceptor compared with the α_1L-adrenoceptor phenotype. Among them, Ro 115–1240 was shown to be an α_1A-specific partial agonist that produced partial contractions through α_1A-adrenoceptors in rat prostate and tail artery, but not in the other LUT tissues and human mesenteric artery. In contrast, P-come 102 showed full agonist activity at α_1A- and α_1L-adrenoceptors, but was less selective than noradrenaline for α_1A-adrenoceptors. Like noradrenaline, P-come 102 was highly potent at inducing contractions in all of the LUT tissues tested. However, the potency and intrinsic activity of P-come 102 were significantly lower than those of noradrenaline in human mesenteric artery.

CONCLUSIONS AND IMPLICATIONS

The α_1A- and α_1L-adrenoceptor phenotypes and LUT α₁-adrenoceptors were demonstrated to have distinct agonist profiles. As adrenergic contractions in LUT are predominantly mediated through α_1L-adrenoceptors, the development of α_1L-selective agonists may provide clinically useful drugs for SUI therapy.     

Sexual reproduction as an adaptation to resist parasites (a review).

Darwinian theory has yet to explain adequately the fact of sex. If males provide little or no aid to offspring, a high (up to 2-fold) extra average fitness has to emerge as a property of a sexual parentage if sex is to be stable. The advantage must presumably come from recombination but has been hard to identify. It may well lie in the necessity to recombine defenses to defeat numerous parasites. A model demonstrating this works best for contesting hosts whose defense polymorphisms are constrained to low mutation rates. A review of the literature shows that the predictions of parasite coevolution fit well with the known ecology of sex. Moreover, parasite coevolution is superior to previous models of the evolution of sex by supporting the stability of sex under the following challenging conditions: very low fecundity, realistic patterns of genotype fitness and changing environment, and frequent mutation to parthenogenesis, even while sex pays the full 2-fold cost.     

Managing subdural fluid collection in infants

INTRODUCTION: The authors classify infantile subdural fluid collection (SFC) into four chronological stages: (I) SFC with arachnoid tear, (II) SFC with inner membrane, (III) SFC with inner and outer membrane, and (IV) subdural hematoma, and discuss the appropriate treatment for each stage. CONCLUSIONS: Fontanel tapping can be used for every stage of SFC, but it is best indicated for stage II. Massive bleeding seldom occurs with punctures made with a small needle. Continuous external drainage is indicated for stages II and III. Although the risk of bleeding decreases even in stage III, this method involves a risk of infection. Burr hole irrigation is usually indicated for stage IV. Implantation of an Ommaya reservoir and endoscopic observation of the SFC cavity along with burr hole irrigation are very useful. A subduroperitoneal shunt cannot be recommended for the treatment of SFC in most cases.     

Early Prognoses of 200 Renal Allografts Harvested from Non–Heart–Beating Cadavers

When the concept of brain death is not widely accepted, the viability of renal allografts of non–heart–beating cadaveric donors is one of the serious concerns for transplant surgeons. At our center, 200 kidneys were harvested from cardiac arrest donors using the regional in situ cooling technique, and they were transplanted into recipients treated with cyclosporine (CS). The ages of donors ranged from 7 months to 67 years. At the bedside a specially designed double balloon catheter, 14F, was inserted into the aorta through the femoral artery just before or immediately after the cardiac arrest. A venous drainage tube was also placed in the vena cava. Following the cardiac arrest, both balloons of the aortic catheter were inflated, and regional in situ cooling with cold Lactate Ringer's solution started using the infusion pump at 20mL/kg/min. In the OR, both kidneys were removed en bloc and preserved in Collins'type solution. They were then transplanted into 200 patients treated with CS and steroid. After the transplant operations, 33 patients (16.5%) had immediate renal function, but 14 grafts (7.0%) were not successful and the patients have never had renal function. When several factors such as donor age, warm ischemic time (WIT; 12.3 ± 14.1 minutes), in situ cooling time (IST; 78.1 ± 18.0 minutes) and total ischemic time (TIT; 619 ± 340 minutes) were associated with the post–transplant renal function, only the donor age had significant correlation both with the posttransplant dialysis period and lowest serum creatine level, as follows: 10.5 days (≤ 40 years) vs. 14.6 days (>40 years); P < 0.05, and 1.16mg/dL (≤ 30 years) vs. 1.83 mg/dL (> 50 years) P < 0.001, respectively. Our findings indicate; 1) Due to the in situ cooling technique, the renal grafts of non–heart–beating cadavers can be expected to have relatively good function in the CS–treated recipients; 2) donor age is instrumental in predicting post–transplant renal function as well as the duration of ATN; 3) WIT, 1ST and TIT have no association with the post–transplant renal function if the duration of renal ischemia is within the acceptable range.